Phosphino-aminophosphines

ABSTRACT

Disclosed are substantially enantiomerically pure bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phosphorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone. The compounds, which have exhibited surprising air stability, are useful as ligands for metal catalysts for asymmetric reactions and have demonstrated excellent results, in particular as rhodium complexes for asymmetric hydrogenation of enamide, itaconate, and α-ketoester compounds. Also disclosed are novel processes for the preparation of the bis-phosphine compounds and novel intermediate compounds useful in the preparation of the bis-phosphine compounds.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplications Serial No. 60/236,564, filed Sep. 29, 2000, and Serial No.60/264,411, filed Jan. 26, 2001.

FIELD OF THE INVENTION

[0002] This invention pertains to novel, substantially enantiomericallypure bis-phosphine compounds possessing the unique feature of havingboth a carbon-bonded phosphine and a nitrogen-bonded phosphine connectedby a divalent chiral group. The compounds are useful as ligands formetal catalysts for asymmetric reactions and have demonstratedsurprising stability as well as excellent results, in particular asrhodium complexes for asymmetric hydrogenation. This invention alsopertains to novel processes and intermediate compounds useful for thepreparation of the bis-phosphine compounds and to compounds comprisingone or more of the bis-phosphine compounds in complex association withone or more Group VIII metals and their use for asymmetrichydrogenation.

BACKGROUND OF THE INVENTION

[0003] Asymmetric catalysis is the most efficient method for thegeneration of products with high enantiomeric purity, as the asymmetryof the catalyst is multiplied many times over in the generation of thechiral product. These chiral products have found numerous applicationsas building blocks for single enantiomer pharmaceuticals as well as insome agrochemicals. The asymmetric catalysts employed can be enzymaticor synthetic in nature. The latter types of catalyst have much greaterpromise than the former due to much greater latitude of applicablereaction types. Synthetic asymmetric catalysts are usually composed of ametal reaction center surrounded by an organic ligand. The ligandusually is generated in high enantiomeric purity, and is the agentinducing the asymmetry. These ligands are, in general, difficult to makeand therefore expensive.

[0004] As is described by Richards, C. J.; Locke, A. J. Tetrahedron:Asymmetry 1998, 9, 2377-2407, asymmetric ferrocene derivatives havefound great utility as ligands for asymmetric catalysis in reactions asvaried as asymmetric hydrogenations, asymmetric Aldol reactions,asymmetric organometallic additions, and asymmetric hydrosilations.These ferrocene species usually are bidentate in nature, using a varietyof ligating species. In the cases where the ligands are phosphines theyinvariably are carbon-linked phosphines. In no cases do theseferrocene-based ligands have heteroatom linkage to the phosphorus atom.Fiorini, M. and Giongo, G. M. J. Mol. Cat. 1979, 5, 303-310, andPracejus, G.; Pracejus, H. Tetrahedron Lett. 1977, 3497-3500, reportthat bis-aminophosphine-based asymmetric ligands afford moderate resultsfor asymmetric hydrogenations (<90% enantiomeric excess—ee), but in nocases have these ligands had either a metallocenyl moiety or a mixtureof carbon and nitrogen-bonded phosphines included therein. Indeed, thereappear to be no reports of chiral, non-racemic, bis-phosphine ligandswhere one phosphine is bonded to three carbon atoms and the other isbonded to two carbons and one nitrogen.

BRIEF SUMMARY OF THE INVENTION

[0005] The novel bis-phosphine compounds provided by our invention aresubstantially enantiomerically pure bis-phosphine compounds comprising asubstantially enantiomerically pure chiral backbone linking twophosphine residues wherein one of the phosphine residues has threephosphorus-carbon bonds and the other phosphine residue has twophophorus-carbon bonds and one phosphorus-nitrogen bond wherein thenitrogen is part of the chiral backbone. These compounds are the firstexamples of chiral bis-phosphines combining a tri-hydrocarbylphosphinewith a dihydrocarbylaminophosphine. These species can be utilized asbidentate ligands for asymmetric catalysis for a variety of reactions.They are of particular interest for asymmetric hydrogenations, and asthe rhodium complex they have afforded hydrogenation products with highenantiomeric excess, in particular for the rhodium-catalyzedhydrogenation of prochiral olefins and ketones. The activity of thesecompounds is readily modified by the choice of the amine substituents.

DETAILED DESCRIPTION

[0006] We have discovered a broad group of novel substantiallyenantiomerically pure bis-phosphine compounds comprised of one phosphineresidue having three phosphorus-carbon bonds and the other having twophosphorus-carbon bonds and one phosphorus-nitrogen bond. Examples ofthe substantially enantiomerically pure, i.e., an enantiomeric excess of90% or greater, compounds include phosphinometallocenylaminophosphineshaving the general formulas 1 and 2 (the enantiomer of 1):

[0007] wherein

[0008] R is selected from substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen;

[0009] R¹, R², R³, R⁴, and R⁵ are independently selected from hydrogen,substituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, substituted and unsubstituted C₃-C₈ cycloalkyl, substituted andunsubstituted C₆-C₂₀ carbocyclic aryl, and substituted and unsubstitutedC₄-C₂₀ heteroaryl wherein the heteroatoms are selected from sulfur,nitrogen, and oxygen;

[0010] n is 0 to 3;

[0011] m is 0 to 5; and

[0012] M is selected from the metals of Groups IVB, VB, VIB, VIIB andVIII.

[0013] The alkyl groups which may be represented by each of R, R¹, R²,R³, R⁴, and R⁵ may be straight- or branched-chain, aliphatic hydrocarbonradicals containing up to about 20 carbon atoms and may be substituted,for example, with one to three groups selected from C₁-C₆-alkoxy, cyano,C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoyloxy, hydroxy, aryl and halogen. Theterms “C₁-C₆-alkoxy”, “C₂-C₆-alkoxycarbonyl”, and “C₂-C₆-alkanoyloxy”are used to denote radicals corresponding to the structures —OR⁶, —CO₂R⁶, and —OCOR⁶, respectively, wherein R⁶ is C₁-C₆-alkyl or substitutedC₁-C₆-alkyl. The term “C₃-C₈-cycloalkyl” is used to denote a saturated,carbocyclic hydrocarbon radical having three to eight carbon atoms. Thearyl groups which each of R, R¹, R², R³, R⁴, and R⁵ may represent mayinclude phenyl, naphthyl, or anthracenyl and phenyl, naphthyl, oranthracenyl substituted with one to three substituents selected fromC₁-C₆-alkyl, substituted C₁-C₆-alkyl, C₆-C₁₀ aryl, substituted C₆-C₁₀aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy,C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy,C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino and —O—R⁷, S—R⁷—SO₂—R⁷,—NHSO₂R⁷ and —NHCO₂R₇, wherein R⁷ is phenyl, naphthyl, or phenyl ornaphthly substituted with one to three groups selected from C₁-C₆-alkyl,C₆-C₁₀ aryl, C₁-C₆-alkoxy and halogen.

[0014] The heteroaryl radicals include a 5- or 6-membered aromatic ringcontaining one to three heteroatoms selected from oxygen, sulfur andnitrogen. Examples of such heteroaryl groups are thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and thelike. The heteroaryl radicals may be substituted, for example, with upto three groups such as C₁-C₆-alkyl, C₁-C₆-alkoxy, substitutedC₁-C₆-alkyl, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy,C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino. The heteroaryl radicalsalso may be substituted with a fused ring system, e.g., a benzo ornaphtho residue, which may be unsubstituted or substituted, for example,with up to three of the groups set forth in the preceding sentence. Theterm “halogen” is used to include fluorine, chlorine, bromine, andiodine.

[0015] The compounds of the invention which presently are preferred haveformulas 1 and 2 wherein R is C, to C₆ alkyl; R¹ is hydrogen or C₁ to C₆alkyl; R² is aryl (preferably phenyl), ethyl, isopropyl, or cyclohexyl;R³ is aryl, most preferably phenyl; R⁴ and R⁵ are hydrogen; and M isiron, ruthenium, or osmium, most preferably iron.

[0016] The compounds of our invention contain both a carbon-linked and anitrogen-linked phosphine. This mixture of features is not known in theliterature (and is particularly not known for metallocene-based ligands)and affords a different electronic environment when complexed to acatalyst metal center as compared to other ligands. In addition, themetallocene-based ligands are readily modifiable by varying R¹ accordingto the choice of the amine used, and thus allow simple modification ofthe reactivity and selectivity of the catalyst prepared from theseligands. An unexpected but particularly advantageous characteristic ofthis metallocene-based phosphino-aminophosphine structural class istheir resistance to oxidative degradation. Indeed, these types ofcompounds retain activity and enantioselectivity (as demonstrated byboth physical properties and trial reactions of their metal complexes)over extended periods at ambient temperature in an air atmosphere,conditions under which many phosphines oxidize to the inactive phosphineoxides.

[0017] Our invention also provides novel processes for the preparationof compounds of formulas 1 and 2. Thus, one embodiment of the processesof the present invention involves a process for the preparation of asubstantially enantiomerically pure compound having formula 1:

[0018] which comprises the steps of:

[0019] (1) contacting a dialkyl amine having formula 3:

[0020]  with a carboxylic anhydride having the formula (R¹⁰CO)₂O toobtain an ester compound having formula 4:

[0021] (2) contacting the ester produced in step (1) with an aminehaving the formula H₂N—R¹ to obtain an intermediate amino-phosphinecompound having formula 5:

[0022] (3) contacting intermediate compound 5 with a halophosphinehaving the formula X—P(R²)₂;

[0023] wherein R, R¹, R², R³, R⁴, R⁵, n, m, and M are definedhereinabove, R⁸ and R⁹ are independently selected from substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, substitutedand unsubstituted C₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀carbocyclic aryl, and substituted and unsubstituted C₄-C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygen,R¹⁰ is a C₁ to C₄ alkyl radical, and X is chlorine, bromine, or iodine.The compounds of formula 2 may be prepared when dialkylamine havingformula 6:

[0024] is used as the starting material affording intermediates 7 and 8analogous to 4 and 5, respectively.

[0025] In the first step of the process, dialkylamine reactant compound3 is contacted with a carboxylic anhydride. The amount of anhydride usedmay be about 1 to 100 moles, preferably about 2 to 10 moles, per mole ofdialkylamine reactant 3. Although the carboxylic anhydride may containup to about 8 carbon atoms, acetic anhydride is particularly preferred.The first step of the process may be carried out at a temperaturebetween about 20° C. and the boiling point of the anhydride, preferablyabout 80 to 120° C. While an inert solvent may be used in step (1), sucha solvent is not essential and the carboxylic anhydride may function asboth solvent and reactant. At the completion of the first step, theester intermediate may be isolated for use in the second step byconventional procedures such as crystallization or removing thecarboxylic anhydride and any extraneous solvent present, e.g., bydistillation.

[0026] Dialkylamine reactant compounds 3 can be prepared in highenantiomeric purity by several known methods. For example, precursor 9having the formula:

[0027] can be prepared in high enantiomeric purity using the proceduresdescribed by Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.;Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389-5393; Armstrong, D. W.; DeMond,W.; Czech, B. P. Anal. Chem. 1985, 57, 481-484; and Boaz, N. W.Tetrahedron Lefters 1989, 30, 2061-2064. Precursor 9 then can beconverted by known procedures to dialkylamine reactant 3, e.g., usingthe procedures described in Hayashi, T. et al. Bull Chem. Soc. Jpn.1980, 53, 1130-1151; and the references mentioned in the precedingsentence. The enantiomeric species 6 can be prepared in a like manner.

[0028] In the second step of the process, the ester intermediateobtained from step (1) is contacted and reacted with an amine having theformula H₂NR¹ in the presence of a C₁ to C₄ alkanol solvent, preferablymethanol or 2-propanol. The second step may be carried out at atemperature between 20° C. and the boiling point of the solvent,preferably about 25 to 50° C. The mole ratio of the amine:esterintermediate 4 (or 7) typically is in the range of about 1:1 to 25:1.Intermediate 5 (or 8) may be recovered for use in step (3) byconventional procedures such as extractive purification orcrystallization.

[0029] In the third step of our novel process, intermediate 5 (or 8) iscontacted and reacted with a halophosphine of the formula XPR² ₂ whereinX is chlorine, bromine, or iodine using a halophosphine:intermediate 5(or 8) mole ratio in the range of about 0.8:1 to 1.3:1. The reaction ofstep (3) is carried out in the presence of an acid acceptor such as atertiary amine, e.g., trialkylamines containing a total of 3 to 15carbon atoms, pyridine, substituted pyridines and the like. The amountof acid acceptor used normally is at least 1 mole of acid acceptor permole of halophosphine employed and up to 5 moles of acid acceptor permole of halophosphine. Step (3) is carried out in the presence of aninert solvent. Examples of inert solvents include, but are not limitedto, non-polar, aprotic solvents such as aliphatic and aromatichydrocarbons containing 6 to 10 carbon atoms, e.g., hexane, heptane,octane, toluene, the various xylene isomers and mixtures thereof, andthe like; halogenated, e.g., chlorinated, hydrocarbons containing up toabout 6 carbon atoms such as dichloromethane, chloroform,tetrachloroethylene, chorobenzene and the like; and cyclic and acyclicethers containing from about 4 to 8 carbon atoms, e.g., tert-butylmethyl ether, diisopropyl ether, tetrahydrofuran and the like. The acidacceptor and solvent particularly preferred are triethylamine andtoluene, respectively. Step (3) may be carried out at a temperaturebetween about −20° C. and the boiling point of the solvent, preferablyabout 0 to 30° C.

[0030] Intermediate amino-phosphine compounds 5 and 8 are novelcompounds and constitute an additional embodiment of our invention. Alsoincluded within the scope of the present invention arecatalytically-active compounds comprising one or more substantiallyenantiomerically pure, bis-phosphine compounds comprising asubstantially enantiomerically pure chiral backbone linking twophosphine residues wherein one of the phosphine residues has threephosphorus-carbon bonds and the other phosphine residue has twophophorus-carbon bonds and one phosphorus-nitrogen bond wherein thenitrogen is part of the chiral backbone in complex association with oneor more Group VIII metals, preferably rhodium, iridium or ruthenium.

EXAMPLES

[0031] The novel compounds and processes provided by the presentinvention are further illustrated by the following examples.

Example 1 Preparation of(R)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethylamine (R,S-5a)(R¹=H)

[0032](R)-N,N-Dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine(R,S-3a, R=R⁸=R⁹=methyl, R³=phenyl-Ph, R⁴=R⁵=H, M=Fe))(10.0 g; 22.7mmol) was combined with acetic anhydride (14.25 mL; 150 mmol; 6.7equivalents) in a 250-mL flask. The flask was evacuated and filled withnitrogen ten times and then heated to 1 00C for 2 hours, at which pointthin layer chromatography (tic) analysis indicated no 3a present. Theresidual acetic anhydride was evaporated at reduced pressure to afford asolid mass containing acetate ester R,S-4a. A portion (1.0 g) of acetateester R,S-4a was removed and the remainder was dissolved in isopropanol(200 mL) and treated with concentrated ammonium hydroxide (28% NH₃; 24.3mL; 360 mmol; 17.5 equiv). The reaction mixture was heated to 50° C.overnight to completely consume 4 according to tic analysis. The mixturewas concentrated to small volume at reduced pressure. The residue wasdissolved in ethyl acetate and extracted with 10% aqueous citric acid(3×75 mL). The acidic extracts were neutralized with 4 N NaOH (115 mL)to pH 12 and extracted with ethyl acetate (3×50 mL). The combinedorganic solution was dried with magnesium sulfate and concentrated invacuo to afford 7.34 g (87% yield) of R,S-5a (R¹=hydrogen). S,R-8a wasprepared in the same manner from S,R-6a.

[0033]¹H NMR (CDCl₃) δ 7.6-7.2 (m, 10H); 4.43 (br s, 1H); 4.28 (m, 1H);4.20 (m, 1H); 4.016 (s, 5H); 3.76 (m, 1H); 1.439 (d, 3H, J=6 59 Hz).

Preparation of(S)-N-diphenylphosphino-1-[(R)-2-(diphenylphosphino)-ferrocenyl]ethylamine(S,R-2a) (R¹=H)

[0034] Amine S,R-8a (1.9 g; 4.6 mmol) was dissolved in 11 mL of toluene.Triethylamine (1.3 mL; 9.3 mmol; 2 equivalents) was added. The mixturewas cooled in ice water and degassed with a nitrogen purge for 10minutes. Chlorodiphenylphosphine (860 μL; 4.8 mmol; 1.04 equivalents)was added dropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to almost completely consume 8a andafford a new spot on tic. Heptane (11 mL) was added and the reactionmixture was filtered and the precipitate was washed with toluene. Thefiltrate was concentrated to afford 2a (R¹=hydrogen) contaminated withsome triethylamine hydrochloride. The crude product was triturated with1:1 toluene:heptane (20 mL) at 4° C. for 1 hour. The mixture wasfiltered and the filtrate was concentrated in vacuo to afford 2.6 g ofS,R-2a (95% yield) as an oil. R,S-1a was prepared in the same mannerfrom R,S-5a.

[0035]¹H NMR (CDCl₃) δ 7.8-7.1 (m, 20H); 4.50 (m, 1H); 4.46 (br s, 1H);4.30 (m, 1H); 3.915 (s, 5H); 1.515 (d, 3H, J=6.59 Hz). FDMS: m/z 597.25(M⁺). [α]_(D) ²⁵+233.30 (c 1.12, toluene).

Example 2 Preparation of(S)-N-Methyl-1-[(R)-2-(diphenylphosphino)-ferrocenyl]ethylamine (S,R-8b)(R¹=Me)

[0036](S)-N,N-Dimethyl-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine(S,R-6a)(5.0 g; 11.3 mmol) was combined with acetic anhydride (7.1 mL;75.2 mmol; 6.7 equivalents) in a 100-mL flask. The flask was evacuatedand filled with nitrogen ten times and then heated to 100° C. for 2hours, at which point tic analysis indicated no 6a present. The residualacetic anhydride was evaporated at reduced pressure to afford a solidmass containing acetate ester S,R-7a. This material was dissolved inisopropanol (110 mL) and treated with 40% aqueous methylamine (14.6 mL;170 mmol; 15 equivalents). The reaction mixture was heated to 50° C. for48 hours to completely consume 7a according to tic analysis. The mixturewas concentrated to small volume at reduced pressure. The residue wasdissolved in 1:1 ethyl acetate:heptane and extracted with 10% aqueouscitric acid (4×10 mL). The acidic extracts were neutralized with 2 NNaOH (50 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic solution was dried with magnesium sulfate and concentrated invacuo to afford 4.33 g (90% yield) of S,R-8b (R¹ =methyl) as an orangesolid. R,S-5b was prepared in the same manner from R,S-3a.

[0037]¹H NMR (CDCl₃) δ 7.55 (m, 2H); 7.37 (m, 3H); 7.26 (m, 5H); 4.463(br s, 1H); 4.286 (m, 1H); 4.028 (s, 5H); 3.94 (m, 1H); 3.78 (m, 1H);1.943 (s, 3H); 1.445 (d, 3H, J=6.59 Hz). FDMS: m/z 427 (M⁺).

Preparation of(S)-N-Methyl-N-diphenylphosphino-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethylamine(S,R-2b)(R¹=Me)

[0038] Amine S,R-8b (427 mg; 1.0 mmol) was dissolved in 2.5 mL oftoluene. Triethylamine (0.29 mL; 2.1 mmol; 2.1 equiv) was added. Themixture was cooled in ice water and degassed with an argon purge for 10minutes. Chlorodiphenylphosphine (180 μL; 1.0 mmol; 1.0 equiv) was addeddropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to afford almost complete consumptionof 8b and a new spot on tic. Heptane (2.5 mL) was added and the reactionmixture was filtered and the precipitate was washed with heptane. Thefiltrate was concentrated in vacuo to afford 0.68 g of S,R-2b(R¹=methyl) as a yellow foam. R,S-1b was prepared in the same mannerfrom R,S-5b.

[0039]¹H NMR (CDCl₃) δ 7.65 (m, 2H); 7.4-7.0 (m, 14H); 6.82 (m, 4H);5.006 (m, 1H); 4.502 (brs, 1H); 4.40 (m, 1H); 4.15 (m, 1H); 3.798 (s,5H); 2.148 (d, 3H, J=3.30 Hz); 1.471 (d, 3H, J=687 Hz). FDMS: m/z 611(M⁺). [α]_(D) ²⁵+229.80 (c 1.10, toluene)

Example 3 Preparation of(R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl acetate (R,S-4a)

[0040](R)-N,N-Dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]-ethylamine(R,S-3a)(10.4g; 24.0 mmol) was combined with acetic anhydride (15 mL; 136 mmol; 5.7equiv) in a 100-mL flask. The flask was evacuated and filled withnitrogen ten times and then heated to 100° C. for 2 hours, at whichpoint tlc analysis indicated no 3a present. The residual aceticanhydride was evaporated at reduced pressure to afford acetate R,S-4a.This material could be recrystallized from an ethyl acetate-heptanemixture.

[0041]¹H NMR (CDCl₃) δ 7.52 (m, 2H); 7.37 (m, 3H); 7.3-7.15 (m, 5H);6.206 (q, 1H, J=2.75 Hz); 4. 568 (m, 1H); 4.349 (m, 1H); 4.045 (s, 5H);3.800 (m, 1H); 1.630 (d, 3H, J=6.32 Hz); 1.170 (s, 3H). FDMS: m/z 456(M⁺).

Preparation of(R)-N-Ethyl-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethylamine (R,S-5c)(R¹=Et)

[0042] (R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethyl acetate(R,S-4a) (1.37 g; 3.0 mmol) was slurried in isopropanol (25 mL) andtreated with 70% aqueous ethylamine (3.6 mL; 45 mmol; 15 equivalents).The reaction mixture was heated to 50° C. for two days to completelyconsume 4a according to tlc analysis. The mixture was concentrated tosmall volume at reduced pressure. The residue was dissolved in 1:1 ethylacetate:heptane and extracted with 10% aqueous citric acid (2×25 mL).The acidic extracts were neutralized with 4 N NaOH (25 mL) and extractedwith ethyl acetate (3×25 mL). The combined organic solution was driedwith magnesium sulfate and concentrated in vacuo to afford 1.19 g (90%yield) of R,S-5c (R¹=ethyl) as an orange solid. S,R-8c was prepared inthe same manner from S,R-7a.

[0043]¹H NMR (CDCl₃) δ 7.6-7.2 (m, 1OH); 4.5 (br s, 1H); 4.28 (m, 1H);4.05 (s, 5H); 4.0 (m, 1H); 3.78 (m, 1H); 2.4-2.2 (m, 2H); 1.45 (d, 3H);0.42 (t, 3H).

[0044] Preparation of(R)-N-Ethyl-N-diphenylphosphino-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethylamine(R,S-1c)(R¹=Et)

[0045] Amine R,S-5c (1.1 g; 2.5 mmol) was dissolved in 6 mL of toluene.Triethylamine (0.69 mL; 5.0 mmol; 2.0 equiv) was added. The mixture wascooled in ice water and degassed with an argon purge for 10 minutes.Chlorodiphenylphosphine (470 μL; 2.6 mmol; 1.05 equiv) was addeddropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to afford almost complete consumptionof 5c and a new spot on tic. Heptane (7 mL) was added and the reactionmixture was filtered and the precipitate was washed with toluene andheptane. The filtrate was concentrated and then re-suspended in heptane.This mixture was filtered and concentrated in vacuo to afford 1.41 g(90%) of R,S-1c (R¹=ethyl) as a yellow foam. S,R-2c was prepared in thesame manner from S,R-8c.

[0046]¹H NMR (CDCl₃) δ 7.7-7.05 (m, 18H); 6.987 (m, 2H); 4.766 (br s,1H); 4.7 (m, 1H); 4.405 (brs, 1H); 4.139 (brs, 1H); 3.822 (s, 5H); 2.65(m, 2H); 1.768 (d, 3H, J=6.87 Hz); 0.698 (t, 3H, J=6.87 Hz). FDMS: m/z625.25 (M⁺). [α]_(D) ²⁵−278.3° (c 1.02, toluene).

Example 4 Preparation of(R)-N-Propyl-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethylamine (R,S-5d)(R¹=Pr)

[0047] (R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethyl acetate(R,S-4a)(2.50 g; 5.5 mmol) was dissolved in methanol (45 mL) and treatedwith n-propylamine (2.2 mL; 26.8 mmol; 4.9 equivalents). The reactionmixture was heated to 50° C. for 2 hours to completely consume 4aaccording to tic analysis. The mixture was concentrated to small volumeat reduced pressure. The residue was dissolved in 1:1 ethylacetate:heptane and extracted with 10% aqueous citric acid (3×25 mL).The acidic extracts were neutralized with 4 N NaOH (38 mL) and extractedwith ethyl acetate (3×25 mL). Solid was noted in the organic extracts.This was collected by filtration and air-dried to afford 0.58 g of thecitric acid salt of R,S-5d (R¹=propyl) as orange crystals. The organicsolution was dried with magnesium sulfate and concentrated to afford1.27 g ((51%) of R,S-5d (R¹=propyl) as an oil. S,R-8d was prepared inthe same manner from S,R-7a.

[0048]¹H NMR (CDCl₃) δ 7.6-7.2 (m, 1OH); 4.497 (br s, 1H); 4.290 (br s,1H); 4.025 (s, 5H); 3.764 (brs, 1H); 3.205 (q, 1H, J=7.14 Hz); 2.35-2.1(m, 2H); 1.462 (d, 3H, J=6.59 Hz); 0.9-0.6 (m, 2H); 0.506 (t, 3H, J=7.14Hz).

Preparation of(R)-N-Propyl-N-diphenylhosphino-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine(R,S-1d) (R¹=Pr)

[0049] Amine R,S-5d (400 mg; 0.88 mmol) was dissolved in 2.1 mL oftoluene. Triethylamine (250 μL; 1.8 mmol; 2.0 equiv) was added. Themixture was cooled in ice water and degassed with an nitrogen purge for10 min. Chlorodiphenylphosphine (200 μL; 1.1 mmol; 1.25 equiv) was addeddropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to afford almost complete consumptionof 5d and a new spot on tic. Heptane (5 mL) was added and the reactionmixture was filtered and the precipitate was washed with toluene andheptane. The filtrate was concentrated in vacuo to afford 0.55 g (86%)of R,S-1d (R¹=propyl). S,R-2d was prepared in the same manner fromS,R-8d.

[0050]¹H NMR (CDCl₃) δ 7.65 (m, 2H); 7.5-7.1 (m, 16H); 6.95 (m, 2H);4.75 (br s, 1H); 4.65 (m, 1H); 4.4 (m, 1H); 4.15 (br s, 1H); 3.82 (s,5H); 2.42 (m, 2H); 1.81 (d, 3H); 1.4-1.2 (m, 2H); 0.39 (t, 3H). FDMS:m/z 639.34 (M⁺). [α]_(D) ²⁵−101.4° (c 1.05, toluene).

Example 5 Preparation of(S)-N-Methyl-N-diethylphosphino-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethylamine(S,R-2e, R¹=Me, R²=Et)

[0051] Amine S,R-8b (500 mg; 1.17 mmol) was slurried in 5 mL of toluene.Triethylamine (0.33 mL; 2.34 mmol; 2.0 equiv) was added. The mixture wascooled in ice-water and degassed with an argon purge for 15 minutes.Chlorodiethylphosphine (0.17 mL; 1.40 mmol; 1.2 equiv) was addeddropwise. The reaction mixture was stirred in ice-water for 30 min tocompletely consume 8b according to tic analysis. The reaction mixturewas allowed to warm to ambient temperature overnight. Heptane (10 mL)was added and the reaction mixture was filtered and the precipitate waswashed with heptane. The filtrate was concentrated in vacuo to afford0.59 g (98%) of S,R-2e as a yellow foam.

[0052]¹H NMR (DMSO-d₆) δ 7.53 (m, 2H); 7.40 (m, 3H); 7.18 (m, 3H); 6.969(m, 2H); 4.503 (m, 2H); 4.392 (m, 1H); 3.873 (m, 1H); 3.831 (s, 5H);1.914 (d, 3H, J=3.02 Hz); 1.438 (d, 3H, J=6.87 Hz); 1.3-1.0 (m,4H);0.841 (dd, 2H, J=7.42,15.11 Hz); 0.55-0.4 (m, 2H). FDMS: m/z 515(M⁺).

[0053] [α]_(D) ²⁵+328.9° (c 1.01, toluene).

Example 6 Preparation of(R)-N-Methyl-N-diisopropylphosphino-1-[(s)-2-(diphenylphosphino)ferrocenyl]ethylamine(R,S-1f, R¹=Me, R²=i-Pr)

[0054] Amine R,S-5b (1.00 9; 2.34 mmol) was dissolved in 5 mL oftoluene. Triethylamine (0.65 mL; 4.7 mmol; 2.0 equiv) was added. Themixture was cooled in ice water and degassed with an argon purge for 15minutes. Chlorodiisopropylphosphine (0.39 mL; 2.46 mmol; 1.05 equiv) wasadded dropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to afford partial consumption of 5band a new spot according to tic analysis. The mixture was heated to 50°C. for 18 hours to afford marginally more conversion. Heptane (10 mL)was added and the reaction mixture was filtered and the precipitate waswashed with heptane. The filtrate was concentrated in vacuo and thecrude product was filtered through a pad of alumina, eluting with85:15:5 heptane:ethyl acetate:triethylamine to afford 0.83 g (65%) ofR,S-1f as a yellow foam. S,R-2f was prepared in a similar fashion fromS,R-8b.

[0055]¹H NMR (DMSO-d₆) δ 7.57 (m, 2H); 7.40 (m, 3H); 7.20 (m, 3H); 7.09(m, 2H); 4.538 (br s, 1H); 4.436 (m, 1H); 4.31 (m, 1H); 4.04 (br s, 1H);3.784 (s, 5H); 2.103 (d, 3H, J=2.20 Hz); 1.62 (m, 1H); 1.557 (d, 3H,J=6.87 Hz); 1.34 (m, 1H);0.85-0.60 (m, 12H). FDMS: m/z 543.40 (M⁺).

[0056] [α]_(D) ²⁵−301.9° (c 1.15, toluene).

Example 7 Preparation of(R)-N-Methyl-N-dicyclohexylphosphino-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine(R,S-1g, R¹=Me, R²=c-C₆H₁₁)

[0057] Amine R,S-5b (2.00 g; 4.7 mmol) was dissolved in 10 mL oftoluene. Triethylamine (1.30 mL; 9.4 mmol; 2.0 equiv) was added. Themixture was cooled in ice water and degassed with an argon purge for 15minutes. Chlorodicyclohexylphosphine (1.05 mL; 4.94 mmol; 1.05 equiv)was added dropwise. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight to afford partial consumption of 5band a new spot according to tic analysis. The mixture was heated to 50°C. for 18 hours to afford significantly more conversion. Heptane (20 mL)was added and the reaction mixture was filtered, the precipitate waswashed with heptane, and the combined filtrate and wash wereconcentrated in vacuo. The crude product was filtered through a pad ofalumina, eluting with 85:15:5 heptane:ethyl acetate:triethylamine toafford 1.50 g (52%) of R,S-1g as a yellow foam. S,R-2g was prepared in asimilar fashion from S,R-8b.

[0058]¹H NMR (DMSO-d₆) α 7.60 (m, 2H); 7.415 (m, 3H); 7.19 (m, 3H); 7.04(m, 2H); 4.532 (br s, 1H); 4.442 (m, 1H); 3.312 (m, 1H); 4.112 (br s,1H); 3.712 (s, 5H); 2.143 (d, 3H, J=1.92 Hz); 1.549 (d, 3H, J=6.87 Hz);1.7-0.7 (m, 22H). FDMS: m/z 624 (M⁺). [α]_(D) ²⁵−292.2° (c 1.01,toluene).

[0059] The utilization of diphosphine 1 or 2 requires the complexationof the ligand with a catalytically active metal (“metal”) which is notthe structural metal of the metallocene. The particular metal chosendepends on the desired reaction. There are a large number of possiblereactions of a wide variety of substrates using catalysts based oncompounds 1 and 2, including but not limited to asymmetrichydrogenations, asymmetric reductions, asymmetric hydroborations,asymmetric olefin isomerizations, asymmetric hydrosilations, asymmetricallylations, and asymmetric organometallic additions. The utility ofligands 1 and 2 will be demonstrated through asymmetric hydrogenationreactions of their metal complexes, which is also an embodiment of ourinvention. Thus, the present invention includes a process for thehydrogenation of a hydrogenatable compound which comprises contactingthe hydrogenatable compound with hydrogen in the presence of a catalystcomplex comprising ligands 1 or 2 in complex association with a metal.Although not wishing to be bound to a particular substrate type, theasymmetric hydrogenation of enamide substrates to afford amino acidderivatives is of particular interest in the pharmaceutical industry,and catalysts based on ligands 1 and 2 show particularly highenantioselectivity for these transformations. Enamide compounds that canbe hydrogenated under these circumstances contain the residueC═C(N—C═O)—C═O, such that if this residue is present in thehydrogenatable compound the transformation will proceed with highenantioselectivity.

[0060] The preferred enamide reactants have the general formula 10,

[0061] wherein R¹¹, R¹², and R¹⁴ are independently selected fromhydrogen, substituted and unsubstituted, branched- and straight-chain C,to C₂₀ alkyl, substituted and unsubstituted C₃ to C₈ cycloalkyl,substituted and unsubstituted C₆ to C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄ to C₂₀ heteroaryl wherein theheteroatoms are selected from sulfur, nitrogen, or oxygen; and

[0062] R¹³ is selected from hydrogen, substituted and unsubstituted C₁to C₂₀ alkyl, substituted and unsubstituted C₁ to C₂₀ alkoxy,substituted and unsubstituted C₃ to C₈ cycloalkyl, substituted andunsubstituted C₃ to C₈ cycloalkoxy, substituted and unsubstitutedcarbocyclic C₆ to C₂₀ aryl, substituted and unsubstituted carbocyclic C₆to C₂₀ aryloxy, substituted and unsubstituted C₄ to C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, or oxygenand substituted and unsubstituted C₄ to C₂₀ heteroaryloxy wherein theheteroatoms are selected from sulfur, nitrogen, and oxygen; or R¹³ andR¹⁴ collectively represent a substituted or unsubstituted alkylene groupof 14 chain carbon atoms forming a lactam.

[0063] The enamides reactants having formula 10 can be prepared usingthe methodology described in Schmidt, U.; Griesser, H.; Leitenberger,V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992,487-490.

[0064] The products of the hydrogenation of enamides having formula 10with catalysts based on ligands 1 and 2 are comprised of species withformula 11,

[0065] wherein R¹¹, R¹², R¹³, and R¹⁴ are as defined above. Thesecompounds are generally produced with very high enantioselectivity (>90%ee), with the particular enantiomer produced depending upon whetherligand 1 or ligand 2 is used.

[0066] Catalysts based on ligands 1 and 2 also show highenantioselectivity for the asymmetric hydrogenation of various itaconateand α-ketoester derivatives. The itaconate compounds which may beselectively hydrogenated have general formula 14,

[0067] wherein R¹⁵ is selected from hydrogen, substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, andsubstituted and unsubstituted C₃-C₈ cycloalkyl, and R¹⁶ and R¹⁷ areindependently selected from hydrogen, substituted and unsubstituted,branched- and straight-chain C₁-C₂₀ alkyl, substituted and unsubstitutedC₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl,and substituted and unsubstituted C₄-C₂₀ heteroaryl wherein theheteroatoms are selected from sulfur, nitrogen, and oxygen. Thepreferred itaconate reactants have formula 14 wherein R¹⁵ is hydrogenand R¹⁶ and R¹⁷ are independently selected from hydrogen and C₁-C₁₀alkyl. The itaconate substrates of formula 14 are generally commerciallyavailable or can prepared by methods known to those skilled in the art.

[0068] The products of the hydrogenation of itaconates having formula 14with catalysts based on ligands 1 and 2 are comprised of species withformula 15,

[0069] wherein R¹⁵, R¹⁶, and R¹⁷ are as defined above. These compoundsare generally produced with high enantioselectivity (>80% ee), with theparticular enantiomer produced depending upon whether ligand 1 or ligand2 is used.

[0070] The α-ketoester compounds which may be selectively hydrogenatedhave general formula 16:

[0071] wherein R¹⁸ and R¹⁹ are independently selected from hydrogen,substituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, substituted and unsubstituted C₃-C₈ cycloalkyl, substituted andunsubstituted C₆-C₂₀ carbocyclic aryl, and substituted and unsubstitutedC₄-C₂₀ heteroaryl wherein the heteroatoms are selected from sulfur,nitrogen, and oxygen; or

[0072] R¹⁸ and R¹⁹ may collectively represent a substituted orunsubstituted alkylene group of 14 chain carbon atoms forming anα-ketolactone.

[0073] The α-ketoester substrates of formula 16 are generallycommercially available or can prepared by methods known to those skilledin the art.

[0074] The preferred α-ketoester reactants have formula 16 wherein R¹⁸and R¹⁹ are independently selected from hydrogen, C₁-C₁₀ alkyl, C₃-C₆cycloalkyl, phenyl, and benzyl. The preferred α-ketoester reactants alsoinclude the compounds of formula 16 wherein R¹⁸ and R¹⁹ collectivelyrepresent a substituted or unsubstituted alkylene group of 2-3 chaincarbon atoms forming an α-ketolactone.

[0075] The products of the hydrogenation of α-ketoesters having formula16 with catalysts based on ligands 1 and 2 are comprised of species withformula 17,

[0076] wherein R¹⁸ and R¹⁹ are as defined above. These compounds aregenerally produced with high enantioselectivity (>80% ee), with theparticular enantiomer produced depending upon whether ligand 1 or ligand2 is used.

[0077] For an asymmetric hydrogenation reaction, the metal complexed canbe chosen from the group consisting of rhodium, iridium, or ruthenium,and is most preferably rhodium. The ligand-metal complex can be preparedand isolated, but it is preferable to prepare the complex in situ fromligand 1 or 2 and a metal pre-catalyst. The ligand to metal molar ratiomay be in the range of about 0.5:1 to 5:1, preferably about 1:1 to1.5:1. The amount of complex may vary between 0.00005 and 0.5equivalents based on the reactant compound, with more complex usuallyproviding faster reaction rates. The atmosphere is hydrogen, but mayalso contain other materials that are inert to the reaction conditions.The reaction can be run at atmospheric pressure or at elevated pressure,from 0.5-200 bars gauge (barg). The reaction is run at a temperaturewhich affords a reasonable rate of conversion, which can be as low as−50° C. but is usually between ambient temperature and the boiling point(or apparent boiling point at elevated pressure) of the lowest boilingcomponent of the reaction mixture. The reaction is usually run in thepresence of a solvent chosen from aliphatic hydrocarbons such as hexane,heptane, octane and the like, aromatic hydrocarbons such as toluene,xylenes, and the like, cyclic or acyclic ethers such as tert-butylmethyl ether, diisopropyl ether, tetrahydrofuran and the like, loweralcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanoland the like, halogenated aliphatic or aromatic hydrocarbons such asdichloromethane, tetrachloroethylene, chloroform, chlorobenzene and thelike, dialkyl ketones such as acetone, 2-butanone, 3-pentanone, methylisopropyl ketone, methyl isobutyl ketone and the like, or polar aproticsolvents such as dimethylformamide, dimethyl sulfoxide and the like.

[0078] These reactions are exemplified by the asymmetric hydrogenationreactions of various enamides, itaconates, and α-ketoesters as shownbelow. The amino-acid derivatives generated from the asymmetrichydrogenation of enamide substrates using a rhodium complex formed insitu from ligands 1 or 2 are generally obtained in very highenantiomeric excess (>90% ee), while the succinate and α-hydroxyesterderivatives generated from the asymmetric hydrogenation of,respectively, the itaconate and α-ketoester substrates using a rhodiumcomplex formed in situ from ligands 1 or 2 are generally obtained inhigh enantiomeric excess (>80% ee).

[0079] General Procedure A—Low Pressure Asymmetric Hydrogenation

[0080] Bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate wasplaced into a reaction vessel and purged with argon for 15 minutes. Asolution of the ligand (1 or 2) in anhydrous tetrahydrofuran (THF, 2.0mL) was degassed with Ar for 15 minutes, then added via cannula to thebis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate. This solutionwas stirred at 25° C. under argon for 15 minutes. A solution of enamide10 (0.5 mmol) in anhydrous THF (2.0 mL) was degassed with argon for 20minutes, then added to the catalyst solution via cannula. The solutionwas then flushed with hydrogen and pressurized to 0.69-1.38 bars gauge(10-20 pounds per square inch gauge—psig) hydrogen. Samples were takenand analyzed for enantiomeric excess using standard analyticaltechniques (see below).

[0081] General Procedure B—High Pressure Asymmetric Hydrogenation

[0082] Bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate and theligand (1 or 2) were placed in a high pressure reaction vessel which wassealed and purged with argon. The desired solvent was degassed with Arfor 15 minutes, then 2.0 mL was added to the reaction vessel viasyringe. This solution was stirred at 25° C. under argon for 15 minutes.A solution of the desired substrate (0.5 mmol) in the desired degassedsolvent (2 mL) was then added to the catalyst solution via syringe. Thesubstrate was washed in with 1 mL of the degassed solvent. The solutionwas then purged five times with argon and pressurized with hydrogen tothe desired pressure (6.9-20.7 barg; 100-300 psig) and heated to thedesired temperature. The reactions were run for 6 hours at the desiredtemperature and pressure, and then cooled (if necessary) to ambienttemperature, depressurized, and purged with argon. Samples were takenand analyzed for enantiomeric excess using standard analyticaltechniques (see below).

Example 8 N-Acetyl L-phenylalanine Methyl Ester (S-11a)

[0083] Enamide 10a (R¹¹=phenyl, R¹²=R¹³=methyl, R¹⁴=H) was hydrogenatedaccording to General Procedure A using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 100%conversion to amino acid derivative S-11a (R¹¹=phenyl, R¹²=R¹³=methyl,R¹⁴=H with 99.2% ee as determined by chiral GC analysis.

[0084]¹H NMR (CD₃OD, 400 MHz) δ 7.28-7.16 (m, 5H); 4.64-4.61 (m, 1H);3.65 (s, 3H); 3.13-3.08 (dd, 1H, J=5.5, 13.9 Hz); 2.94-2.88 (dd, 1H,J=8.9, 13.9 Hz); 1.87 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25m×0.25 mm ID, film thickness 0.12 μm, 160° C. for 9 min, 160-185° C. at70° C./min, 185° C. for 5 min, 15 psig He]: t_(R)(R-11a) 7.77 min,t_(R)(S-11a) 8.29 min, t_(R)(10a) 13.24 min.

Example 9 N-Acetyl L-phenylalanine Methyl Ester (S-1 1a) via HighPressure Hydrogenation in THF

[0085] Enamide 10a (R¹¹=phenyl, R¹²=R¹³=methyl, R¹⁴=H) was hydrogenatedaccording to General Procedure B in THF usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-lb (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative S-11a(R¹¹=phenyl, R¹²=R¹³=methyl, R¹⁴=H) with 96.8% ee as determined bychiral GC analysis.

Example 10 N-Acetyl L-phenylalanine methyl ester (S-11a) via HighPressure Hydrogenation in Acetone

[0086] Enamide 10a (R¹=phenyl, R¹²=R¹³=methyl, R¹⁴=H) was hydrogenatedaccording to General Procedure B in acetone usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative S-11a(R¹¹=phenyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.6% ee as determined bychiral GC analysis.

Example 11 N-Acetyl L-phenylalanine (S-11b)

[0087] Enamide 10b (R¹¹=phenyl, R¹²=R¹⁴=H, R¹³=methyl) was hydrogenatedaccording to General Procedure A using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 1 hour to afford 100%conversion to amino acid derivative S-11b (R¹¹=phenyl, R¹²=R¹⁴=H,R¹³=methyl) with 99.4% ee.

[0088] A sample was treated with diazomethane to make the methyl esterbefore analysis. See Example 8 (N-acetyl phenylalanine methyl ester) foranalytical details.

[0089]¹H NMR (CD₃0D, 300 MHz) δ 7.20-7.08 (m, 6H); 4.58-4.54 (dd, 1H,J=5.2, 9.1 Hz); 3.14-3.07 (dd, 1H, J=4.9, 13.9 Hz); 2.88-2.80 (dd, 1H,J=9.1, 14.0 Hz); 1.8 (s, 3H).

Example 12 N-t-Butyloxycarbonyl L-phenylalanine methyl ester (S-11c)

[0090] Enamide 10c (R¹¹=phenyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (3.0 mg; 6.5μmol; 0.013 equiv) and ligand (R,S)-1b (4.4 mg; 7.2 μmol; 0.016 equiv)for 1 hour to afford 100% conversion to amino acid derivative S-11c(R¹¹=phenyl, R¹²=methyl, R¹³ t-butoxy, R¹⁴=H) with 99.5% ee asdetermined by chiral GC analysis. Chiral GC [Chirasil L-Valine (Varian)25 m×0.25 mm ID, film thickness 0.12 μm, 140° C. isothermal, 15 psigHe]: t_(R)(R-11c) 19.14 min, t_(R)(S-11C) 19.66 min, t_(R)(10c) 40.14min.

Example 13 N-Benzamido L-phenylalanine methyl ester (S-11d)

[0091] Enamide 10d (R¹¹=R¹³=phenyl, R¹²=methyl, R¹⁴=H) was hydrogenatedaccording to General Procedure A using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 100%conversion to amino acid derivative S-11d (R¹¹=R¹³=phenyl, R¹²=methyl,R¹⁴=H) with 98.4% ee as determined by chiral GC analysis.

[0092]¹H NMR (CD₃OD, 600 MHz) δ 7.72-7.70 (d, 2H, J=7.3 Hz); 7.50-7.47(m, 1H); 7.40-7.23 (m, 2H); 7.20-7.17 (m, 5H); 4.854.83 (m, 1H); 3.69(s, 3H); 3.65 (s, 1H); 3.29-3.26 (m, 1H); 3.13-3.08 (m, 1H). Chiral GC[Chirasil L-Valine (Varian) 25 m×0.25 mm ID, film thickness 0.12 μm,150° C. isothermal, 15 psig He]: t_(R)(R-11d) 11.69 min, t_(R)(S-11d)12.68 min, t_(R)(10d) 18.5 min.

Example 14 N-Acetyl D-alanine Methyl Ester (R-11e)

[0093] Enamide 10e (R¹¹=R¹⁴=H, R¹²=R¹³=methyl) was hydrogenatedaccording to General Procedure A using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (5.8 mg; 12.5 μmol; 0.025 equiv) and ligand(S,R)-2b (9.3 mg; 15 μmol; 0.03 equiv) for 1 hour to afford 100%conversion to amino acid derivative R-11e (R¹¹=R¹⁴=H, R¹²=R¹³=methyl)with 98.4% ee as determined by chiral GC analysis.

[0094]¹H NMR (CD₃OD, 600 MHz) δ 4.42-4.38 (dd, 1H, J=7.3,14.7 Hz); 3.72(s, 3H); 1.98 (s, 3H); 1.38-1.37 (d, 3H, J=7.3 Hz). Chiral GC[Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, 0.25 um film thickness,40-100° C. at 70° C./min, 100° C. for 15 min, 100-170° C. at 15° C/min,170° C. for 7 min, 6 psig He for 6 min, 6-20 psig He at 80 psig/min, 20psig for 22 min]: t_(R)(R-11e) 19.36 min, t_(R)(S-11e) 19.12 min,t_(R)(10e) 17.91 min.

Example 15 N-Acetyl L-alanine methyl ester (S-11e) via High PressureHydrogenation in Acetone

[0095] Enamide 10e (R¹¹=R¹⁴=H, R¹²=R¹³=methyl) was hydrogenatedaccording to General Procedure B in acetone usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for1 hour to afford 100% conversion to amino acid derivative R-11e(R¹¹=R¹⁴=H, R¹²=R¹³=methyl) with 95.2% ee as determined by chiral GCanalysis.

Example 16 N-Acetyl D-alanine (R-11f)

[0096] Enamide 1Of (R¹¹=R¹²=R¹⁴=H, R¹³=methyl) was hydrogenatedaccording to General Procedure A using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2b (3.7 mg; 6 μmol; 0.012 equiv) for 24 hours to afford 100%conversion to amino acid derivative R-11f (R¹¹=R¹²=R¹⁴=H, R¹³=methyl)with 96.1% ee.

[0097] A sample was treated with diazomethane to make the methyl esterbefore analysis. See Example 14 (N-acetyl alanine methyl ester) foranalytical details.

Example 17 N-Benzyloxycarbonyl L-alanine methyl ester (S-11g)

[0098] Enamide 10g (R¹¹=R¹⁴=H, R¹²=methyl, R¹³=benzyloxy) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for1 hour to afford 56% conversion to amino acid derivative S-11g(R¹¹=R¹⁴=H, R¹²=methyl, R¹³=benzyloxy) with 98.8% ee as determined bychiral GC analysis.

[0099]¹H NMR (CDCl₃, 600MHz) δ 7.33-7.26 (m, 5H); 5.07 (s, 2H); 4.234.19(m, 1H); 3.69 (s, 3H); 1.36-1.34 (d, 3H, J=7.3 Hz). Chiral GC [ChirasilL-Valine (Varian) 25 m×0.25 mm ID, film thickness 0.12 μm, 150° C.isothermal, 15 psig He]: t_(R)(R-11g) 11.37 min, t_(R)(S-11g) 11.70 min,t_(R)(10g) 10.10 min.

Example 18 N-Benzyloxycarbonyl L-homophenylalanine Ethyl Ester (S-11h)

[0100] Enamide 1Oh (R¹¹=benzyl, R¹²=ethyl, R¹³=benzyloxy, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) toafford >99% conversion to amino acid derivative S-11h (R¹¹=benzyl,R¹²=ethyl, R¹³=benzyloxy, R¹⁴=H) with 98.1% ee as determined by chiralHPLC analysis.

[0101]¹H NMR (CDCl₃, 400 MHz) δ 7.37-7.15 (m, 10H); 5.38-5.36 (d, 1H,J=7.9 Hz); 5.12 (s, 2H); 4.444.39 (dd, 1H, J=7.6, 13.0 Hz); 4.20-4.15(dd, 2H, J=7.0, 14.3 Hz); 2.73-2.60 (m, 2H); 2.27-2.14 (m, 1H);2.02-1.93 (m, 1H); 1.28-1.25 (t, 3H, J=7.0 Hz). A chiral normal-phaseHPLC separation of the two enantiomers was developed using a Cyclobond I2000 SN column (Advanced Separation Technologies, Inc.). Ultravioletdetection was used at a wavelength of 210 nm. The mobile phase was 9713heptane/isopropanol (v/v). t_(R)(R-11h) 28.93 min, t_(R)(S-11h) 30.99min, t_(R)(10h) 33.39 min.

Example 19 N-Acetyl L-4-chlorophenylalanine Methyl Ester (S-11i)

[0102] Enamide 10i (R¹¹=4-chlorophenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (4.6 mg; 10μmol; 0.02 equiv) and ligand (R,S)-11b (7.4 mg; 12 μmol; 0.024 equiv)for 2 hours to afford 100% conversion to amino acid derivative S-11i(R¹¹=4-chlorophenyl, R¹²=R¹³=methyl, R¹⁴=H) with 98.8% ee as determinedby chiral GC analysis.

[0103]¹H NMR (CD₃OD, 600 MHz) 7.27-7.25 (d, 2H, J=8.7 Hz); 7.18-7.16 (d,2H, J=8.7 Hz); 4.644.62 (dd, 1H, J=5.5, 9.2 Hz); 3.70 (s, 1H); 3.67 (s,3H), 3.13-3.09 (dd, 1H, J=5.5,13.7 Hz); 2.93-2.89 (dd, 1H, J=9.2, 13.9Hz); 1.88 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m×0.25 mmID, film thickness 0.12 μm, 175° C. isothermal, 20 psig He]:t_(R)(R-11i) 7.29 min, t_(R)(S-11i) 7.76 min, t_(R)(10i) 15.72 min.

Example 20 N-Acetyl L-4-chlorophenylalanine methyl ester (S-11i) viaHigh Pressure Hydrogenation in THF

[0104] Enamide 10i (R¹¹=4-chlorophenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure B in THF usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative S-11i(R¹¹=4-chlorophenyl, R¹²=R¹³=methyl, R¹⁴=H) with 96.2% ee as determinedby chiral GC analysis.

Example 21 N-Acetyl L-4-cyanophenylalanine methyl ester (S-11j)

[0105] Enamide 10j (R¹¹=4-cyanophenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for1 hour to afford 100% conversion to amino acid derivative S-11j(R¹¹=4-cyanophenyl, R¹²=R¹³=methyl, R¹⁴=H) with 99.0% ee as determinedby chiral GC analysis. Chiral GC [Chirasil L-Valine (Varian) 25 m×0.25mm ID, film thickness 0.12 μm, 190° C. isothermal, 20 psig He]:t_(R)(R-11j) 8.73 min, t_(R)(S-11j) 9.17 min.

Example 22 N-Acetyl L-4-methoxyphenylalanine methyl ester (S-11k)

[0106] Enamide 10k (R¹¹=4-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (4.6 mg; 10μmol; 0.02 equiv) and ligand (R,S)-1b (7.4 mg; 12 μmol; 0.024 equiv) for30 minutes to afford 90% conversion to amino acid derivative S-11k(R¹¹=4-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.9% ee as determinedby chiral GC analysis.

[0107]¹H NMR (CD₃OD, 400 MHz) δ 7.09-7.07 (d, 2H, J=8.9 Hz); 6.82-6.80(d, 2H, J=8.9 Hz); 4.59-4.56 (dd, 1H J=5.8, 8.9 Hz); 3.73 (s, 3H); 3.70(s, 1H); 3.65 (s, 3H); 3.06-3.01 (dd, 1H, J=5.8, 13.7 Hz); 2.88-2.82(dd, 1H, J=8.9, 13.9 Hz); 1.88 (s, 3H). Chiral GC [Chirasil L-Valine(Varian) 25 m×0.25 mm ID, film thickness 0.12 μm, 1850C isothermal, 20psig He]: t_(R)(R-11k) 6.04 min, t_(R)(S-11k) 6.32 min, t_(R)(10k) 15.13min.

Example 23 N-Acetyl L-4-methoxyphenylalanine Methyl Ester (S-11k) viaHigh Pressure Hydrogenation in THF

[0108] Enamide 10k (R¹¹=4-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure B in THF usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative S-11k(R¹¹=4-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.3% ee as determinedby chiral GC analysis.

Example 24 N-Acetyl L-3-methoxyphenylalanine Methyl Ester (S-11m)

[0109] Enamide 10m (R¹¹=3-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (4.6 mg; 10μmol; 0.02 equiv) and ligand (R,S)-1b (7.4 mg; 12 μmol; 0.024 equiv) for30 minutes to afford 100% conversion to amino acid derivative S-11m(R¹¹=3-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) with 98.0% ee as determinedby chiral GC analysis.

[0110]¹H NMR (CD₃OD, 400 MHz) δ 7.19-7.15 (t, 1H, J=7.9 Hz,); 6.78-6.74(m, 3H); 4.664.62 (dd, 1H, J=5.5, 9.0 Hz); 3.75 (s, 3H); 3.72-3.69 (m,1H); 3.67 (s, 3H); 3.12-3.07 (dd, 1H, J=5.8, 13.9 Hz); 2.92-2.88 (dd,1H, J=8.9,13.7 Hz); 1.89 (s, 3H). Chiral GC [Chirasil L-Valine (Varian)25 m×0.25 mm ID, film thickness 0.12 μm, 185° C. isothermal, 20 psigHe]: t_(R)(R-11m) 7.73 min, t_(R)(S-11m) 8.18 min.

Example 25 N-Acetyl L-2-methoxyphenylalanine methyl ester (S-11n)

[0111] Enamide 10n (R¹¹=2-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (4.6 mg; 10μmol; 0.02 equiv) and ligand (R,S)-1b (7.4 mg; 12 μmol; 0.024 equiv) for2 hours to afford 99.5% conversion to amino acid derivative S-11n(R=2-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.7% ee as determinedby chiral GC analysis.

[0112]¹H NMR (CD₃OD, 600 MHz) δ7.21-7.19 (t, 1H, J=7.3 Hz); 7.06-7.05(d, 1H, J=7.3 Hz); 6.92-6.90 (d, 1H, J=7.8 Hz); 6.84-6.82 (t, 1H, J=7.8Hz); 4.674.66 (m, 1H); 3.82 (s, 3H); 3.70 (s, 1H); 3.63 (s, 3H);3.16-3.13 (dd, 1H, J=6.0,13.5 Hz); 2.90-2.86 (dd, 1H, J=8.7,13.3 Hz);1.86 (s, 3H). Chiral GC [Chirasil L-Valine (Varian) 25 m×0.25 mm ID,film thickness 0.12 μm, 185° C. isothermal, 20 psig He]: t_(R)(R-11n)4.87 min, t_(R)(S-11n) 5.07 min, t_(R)(10n) 8.96 min.

Example 26 N-Acetyl L-2-methoxyphenylalanine methyl ester (S-11n) viaHigh Pressure Hydrogenation in THF

[0113] Enamide 10n (R¹¹=2-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure B in THF usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative S-11n(R¹¹=2-methoxyphenyl, R¹²=R¹³=methyl, R¹⁴=H) with 96.7% ee as determinedby chiral GC analysis.

Example 27 N-Acetyl L-4-nitrophenylalanine Methyl Ester (S-10)

[0114] Enamide 10o (R¹¹=4-nitrophenyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for30 minutes to afford 100% conversion to amino acid derivative S-11o(R¹¹=4-nitrophenyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.7% ee as determinedby chiral GC analysis.

[0115]¹H NMR (CD₃OD, 400 MHz) δ8.15-8.13 (d, 2H, J=8.9 Hz,); 7.45-7.43(d, 2,H J=8.6 Hz); 4.75-4.71 (dd, 1H, J=5.5, 9.2 Hz,); 3.69 (s, 3H);3.67 (s, 1H); 3.30-3.25 (m, 1H); 3.08-3.02 (m, 1H); 1.88 (s, 3H). ChiralGC [Chirasil L-Valine (Varian) 25 m×0.25 mm ID, film thickness 0.12 μm,185° C. isothermal, 20 psig He]: t_(R)(R-11o) 15.73 min, t_(R)(S-11o)16.79 min.

Example 28 N-t-Butyloxycarbonyl L-3-furanylalanine Methyl Ester (S-11p)

[0116] Enamide 10p (R¹¹=3-furanyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 98% conversion to amino acid derivative S-11p(R¹¹=3-furanyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) with 97.2% ee asdetermined by chiral GC analysis.

[0117]¹H NMR (CDCl₃, 300 MHz) δ7.36 (s, 1H); 7.25 (s, 1H); 6.21 (s, 1H);5.12-5.09 (m, 1H); 4.53-4.51 (m, 1H); 3.73 (s, 3H); 2.93-2.92 (m, 2H);1.44 (s, 9H). Chiral GC [Chirasil L-Valine (Varian) 25 m×0.25 mm ID,film thickness 0.12 μm, 140° C. isothermal, 20 psig He]: t_(R)(R-11p)7.61 min, t_(R)(S-11p) 7.89 min, t_(R)(10P) 17.97 min.

Example 29 N-Benzamido D-3-furanylalanine Methyl Ester (R-11q)

[0118] Enamide 10q (R¹¹=3-furanyl, R¹²=methyl, R¹³=phenyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (S,R)-2b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 100% conversion to amino acid derivative R-11q(R¹¹=3-furanyl, R¹²=methyl, R¹³=phenyl, R¹⁴=H) with 96.6% ee asdetermined by chiral GC analysis.

[0119]¹H NMR (CD₃OD, 400 MHz) δ7.77-7.75 (m, 2H); 7.53-7.36 (m, 6H);4.79-4.75 (dd, 1H, J=5.2, 9.3 Hz); 3.72 (s, 3H); 3.69 (s, 1H); 3.11-3.06(dd, 1H, J=5.2, 14.6 Hz); 2.99-2.93 (dd, 1H, J=9.5,14.6 Hz). Chiral GC[Chirasil L-Valine (Varian) 25 m×0.25 mm ID, film thickness 0.12 μm,175° C. isothermal, 20 psig He]: t_(R)(R-11q) 12.57 min, t_(R)(S-11q)13.29 min, t_(R)(10q) 9.39 min.

Example 30 N-t-Butyloxycarbonyl L-cyclopropylalanine methyl ester(S-11r)

[0120] Enamide 10r (R¹¹=cyclopropyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H)was hydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 90% conversion to amino acid derivative S-11r(R¹¹=cyclopropyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) with 98.6% ee asdetermined by chiral GC analysis.

[0121]¹H NMR (CDCl₃, 300 MHz) δ5.22-5.20 (m, 1H); 4.41-4.34 (m, 1H);3.74 (s, 3H); 1.69-1.64 (t, 2H, J=6.6 Hz); 0.73-0.67 (m, 1H); 0.51-0.44(m, 2H); 0.10-0.05 (m, 2H). Chiral GC [Chirasil L-Valine (Varian) 25m×0.25 mm ID, film thickness 0.12 μm, 175° C. isothermal, 15 psig He]:t_(R)(R-11r) 14.59 min, t_(R)(S-11r) 15.21 min, t_(R)(10r) 26.34 min.

Example 31 N-Benzamido D-cyclopropylalanine Methyl Ester (R-11s)

[0122] Enamide 10s (R¹¹=cyclopropyl, R¹²=methyl, R¹³=phenyl, R¹⁴=H) washydrogenated according to General Procedure A usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (S,R)-2b (3.7 mg; 6 μmol; 0.012 equiv) for24 hours to afford 100% conversion to amino acid derivative R-1 Is(R¹¹=cyclopropyl, R¹²=methyl, R¹³=phenyl, R¹⁴=H) with 91.6% ee asdetermined by chiral GC analysis.

[0123]¹H NMR (CDCl₃, 300 MHz) δ7.80-7.76 (m, 2H); 7.50-7.36 (m, 3H);4.62-4.57 (m, 1H); 3.66 (s, 3H); 1.81-1.75 (m, 1H); 1.69-1.63 (m, 1H);0.80-0.75 (m, 1H); 0.45-0.39 (m, 2H); 0.09-0.04 (m, 2H). ¹³C NMR (CDCl₃,75 MHz) δ 133.0,129.7, 128.7, 55.3, 52.9, 37.5, 23.6, 9.1, 5.4, 4.8.Chiral GC [Chirasil L-Valine (Varian) 25 m×0.25 mm ID, film thickness0.12 μm, 175° C. isothermal, 20 psig He]: t_(R)(R-11s) 10.76 min,t_(R)(S-11s) 11.18 min, t_(R)(10S) 17.73 min.

Example 32 N-t-Butyloxycarbonyl L-cyclopropylalanine Benzyl Ester(S-11t)

[0124] Enamide 10t (R¹¹=cyclopropyl, R¹²=benzyl, R¹³=t-butoxy, R¹⁴=H)was hydrogenated according to General Procedure A in acetone as solventusing bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg;5 μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv)for 1 hour to afford 94% conversion to amino acid derivative S-11 t(R¹¹=cyclopropyl, R¹²=benzyl, R¹³=t-butoxy, R¹⁴=H) with >99% ee asdetermined by chiral GC analysis.

[0125]¹H NMR (CDCl₃, 300MHz) δ 7.414.30 (m, 5H); 5.13-5.12 (m, 1H); 5.02(s, 2H); 1.70-1.60 (m, 2H); 1.45 (s, 9H); 0.69-0.61 (m, 1H); 0.42-0.39(m, 2H); 0.02-0.01 (m, 2H). Chiral GC [Chirasil L-Valine (Varian) 25m×0.25 mm ID, film thickness 0.12 μm, 175° C. isothermal, 15 psig He]:t_(R)(R-11t) 15.03 min, t_(R)(S-11t) 15.48 min, t_(R)(10t) 25.98 min.

Example 33 N-t-Butyloxycarbonyl L-cyclopropylalanine Benzyl Ester(S-11t) via High Pressure Hydrogenation in Acetone

[0126] Enamide 10t (R¹¹=cyclopropyl, R¹²=benzyl, R¹³=t-butoxy, R¹⁴=H)was hydrogenated according to General Procedure B in acetone as solventusing bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg;5 μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv)for 1 hour to afford 100% conversion to amino acid derivative S-11t(R¹¹=cyclopropyl, R¹²=benzyl, R¹³=t-butoxy, R¹⁴=H) with 95.5% ee asdetermined by chiral GC analysis.

Example 34 N-Acetyl 1-Naphthylalanine methyl ester (S-11u)

[0127] Enamide 10u (R¹¹=1-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A in THF as solvent usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1 b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford >95% conversion to amino acid derivative S-11u(R¹¹=1-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) with 99.3% ee as determined bychiral GC analysis.

[0128]¹H NMR (CDCl₃, 300 MHz) δ 8.083 (d, 1H, J=8.24 Hz); 7.855 (d, 1H,J=7.69 Hz); 7.769 (d, 1H, J=7.97 Hz); 7.510 (m(5), 2H, J=7.97 Hz); 7.385(t, 1H, J=7.14 Hz); 7.230 (d, 1H, J=6.87 Hz); 5.98 (br s, 1H); 5.017 (q,1H, J=6.59 Hz); 3.626 (s, 3H); 3.57 (m, 2H); 1.926 (s, 3H). Chiral GC[Chirasil L-Valine (Varian) 25 m×0.25 mm ID, film thickness 0.12 μm,185° C. for 22 min, 185-195° C. at 1⁰° C/min, 195° C. for 17 min, 15psig He]: t_(R)(R-11u) 18.83 min, t_(R)(S-11U) 19.76 min.

Example 35 N-Acetyl 1-Naphthylalanine Methyl Ester (S-11u) via HighPressure Hydrogenation

[0129] Enamide 10u (R¹¹=1-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure B in acetone as solventusing bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg;5 μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv)for 6 hours to afford >95% conversion to amino acid derivative S-11u(R¹¹=1-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.4% ee as determined bychiral GC analysis.

Example 36 N-t-Butyloxycarbonyl 1-Naphthylalanine methyl ester (S-11v)

[0130] Enamide 10v (R¹¹=1-naphthyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) washydrogenated according to General Procedure A in THF as solvent usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford >95% conversion to amino acid derivative S-11v(R¹¹=1-naphthyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) with 98.2% ee asdetermined by chiral HPLC analysis.

[0131]¹H NMR (CDCl₃, 300 MHz) δ8.075 (d, 1H, J=7.96 Hz); 7.858 (d, 1H,J=7.69 Hz); 7.767 (d, 1H, J=8.24 Hz); 7.512 (m(5), 2H, J=7.97 Hz); 7.391(t, 1H, J=7.14 Hz); 7.27 (m, 1H); 5.057 (brd, 1H, J=7.69 Hz); 4.719 (q,1H, J=7.69 Hz); 3.744 (s, 3H); 3.7-3.4 (m, 2H); 1.395 (s, 9H). ChiralHPLC [Chiralcel OD-H (Diacel Chemical), 250×4.6 mm, 95:5hexane:isopropanol, 1 mL/min, λ=254 nm]: t_(R)(R-11v) 14.05 min,t_(R)(S-11V) 17.64 min.

Example 37 N-Acetyl 2-Naphthylalanine methyl ester (S-11w)

[0132] Enamide 10w (R¹¹=2-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure A in THF as solvent usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for1 hour to afford >95% conversion to amino acid derivative S-11w(R¹¹=2-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) with 98.1% ee as determined bychiral GC analysis.

[0133]¹H NMR (CDCl₃, 300 MHz) δ7.85-7.75 (m, 3H); 7.553 (s, 1H); 7.47(m, 2H); 7.218 (d, 1H, J=8.52 Hz); 6.01 (brs, 1H); 4.966 (q, 1H, J=6.04Hz); 3.727 (s, 3H); 3.314 (dd, 1H, J=5.77, 13,74 Hz); 3.244 (dd, 1H,J=6.04, 14.01 Hz); 1.973 (s, 3H). Chiral GC [Chirasil L-Valine (Varian)25 m×0.25 mm ID, film thickness 0.12 μm, 185° C. isothermal, 15 psigHe]: t_(R)(R-11w) 22.02 min, t_(R)(S-11w) 23.26 min.

Example 38 N-Acetyl 2-Naphthylalanine Methyl Ester (S-11w) via HighPressure Hydrogenation

[0134] Enamide 10w (R¹¹=2-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) washydrogenated according to General Procedure B in acetone as solventusing bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg;5 μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv)for 6 hours to afford >95% conversion to amino acid derivative S-11w(R¹¹=2-naphthyl, R¹²=R¹³=methyl, R¹⁴=H) with 97.6% ee as determined bychiral GC analysis.

Example 39 N-t-Butyloxycarbonyl 2-Naphthylalanine Methyl Ester (S-11x)

[0135] Enamide 10x (R¹¹=2-naphthyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) washydrogenated according to General Procedure A in THF as solvent usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 97% conversion to amino acid derivative S-11x(R¹¹=2-naphthyl, R¹²=methyl, R¹³=t-butoxy, R¹⁴=H) with 97.4% ee asdetermined by chiral HPLC analysis. ¹H NMR (CDCl₃, 300 MHz) δ 7.80 (m,3H); 7.586 (s, 1H,); 7.45 (m, 2H); 7.26 (m, 1H); 5.000 (brd, 1H, J=7.14Hz); 4.677 (q, 1H, J=6.87 Hz); 3.713 (s, 3H); 3.35-3.15 (m, 2H); 1.399(s, 9H). Chiral HPLC [Chiralcel OD-H (Diacel Chemical), 250×4.6 mm, 95:5hexane:isopropanol, 1 mumin, λ=254 nm]: t_(R)(R-11x) 12.86 min,t_(R)(S-11x) 14.41 min.

Example 40

[0136]

[0137] Enamide 10a was hydrogenated according to General Procedure A for1 hour using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate(2.3 mg; 5 μmol; 0.01 equiv) and the ligands indicated below (6 μmol;0.012 equiv) to afford in all cases 100% conversion to amino acidderivative 11a with the indicated enantiomeric purity as determined bychiral GC analysis (see Example 8 for analytical details). Ligand 11aConfiguration 11a ee (%) (R,S)-1a S 97.2 (R,S)-1b S 99.1 (R,S)-1c S 94.3(S,R)-2d R 93.3

Example 41

[0138]

[0139] Enamide 10a was hydrogenated according to General Procedure A for1 hour using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonateand ligand (R,S)-1b in the indicated solvent to afford amino acidderivative S-11a with the conversion and enantiomeric excess indicated(see Example 8 for analytical details). Solvent % ee % conv. Solvent %ee % conv. THF 99.1 100 EtOAc 98.5 100  MeOH 98.5 100 TBME >99   2%iPrOH 97.7 100 DMF 96.5 25 Acetone 98.3  97 DMSO 94.4 15 PhMe 97.4 100CH₂Cl₂ 97.9 99

[0140] Tetrahydrofuran (THF), toluene (PhMe), t-butyl methyl ether(TBME), and methanol (MeOH) were anhydrous and used as received.Dichloromethane (CH₂Cl₂), acetone, 2-propanol (iPrOH), ethyl acetate(EtOAc), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) werenot strictly anhydrous nor dried prior to use.

Example 42

[0141]

[0142] (R,S)-1b was placed in an uncapped vial and left exposed toambient conditions (25° C.) for seven months prior to use.Bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol, 0.01 equiv) was placed into a reaction vessel and purged withargon for 15 minutes. A solution of (R,S)-1b (3.7 mg; 6 μmol, 0.012equiv) in anhydrous THF (2.0 mL) was degassed with argon for 15 minutes,then added via cannula to the bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate. This solution was stirred at 25° C. underargon for 15 minutes. A solution of enamide 10a (0.5 mmol) in anhydrousTHF (2.0 mL) was degassed with argon for 20 minutes, then added to thecatalyst solution via cannula. The solution was then flushed withhydrogen and pressurized to 0.69-1.38 barg (10-20 psig) hydrogen. Thereaction was depressurized after 1 hour. N-acetyl L-phenylalanine methylester (S-11a) was isolated in 100% yield and 98.8% ee (see Example 8 foranalytical details).

Example 43

[0143]

[0144] Enamide 10a (5.48 g; 25.0 mmol) was added to a drynitrogen-purged Fisher-Porter bottle. Argon-degassed methanol (32 mL)was added to afford a homogeneous solution which was purged with argonfor 10 minutes. The bottle was fitted with a pressure head and evacuatedand filled with argon ten times. To a dry 25-mL flask was addedbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (1.2 mg; 0.0025mmol; 0.0001 equiv) and ligand (R,S)-1b (1.7 mg, 0.0028 mmol; 0.00011equiv) which had been open to the air at ambient temperature for morethan seven months. The flask was purged with argon and 2 mL ofargon-degassed THF was added to afford a homogeneous solution. This wasallowed to stand for 15 min and then added via a gas-tight syringe tothe Fisher-Porter bottle containing the methanolic solution of 10a. Thebottle was evacuated and filled with argon ten times, and then evacuatedand filled with hydrogen 5 times. The bottle was pressurized with 45psig hydrogen, sealed, and stirred vigorously at ambient temperature.Hydrogen uptake was immediate and rapid, and was essentially completeafter 70 minutes. The reaction mixture was evacuated and filled withargon five times and then depressurized. The reaction mixture wassampled and analyzed by chiral GC to indicate 96.3% conversion to S-11awith 96.8% ee. The reaction mixture was evaporated to afford 5.27 g(95%) of product. See Example 8 for analytical details.

Example 44 Hydrogenation of Enamide 12 to Produce Ester 13 Using Ligand(R,S)-1b

[0145] A Fischer-Porter tube was charged with ligand (R,S)-1b (22 mg,0.036 mmol; 0.064 equivalents) and anhydrous THF (4.0 mL) under an argonatmosphere. Argon was bubbled through the solution for 20 minutes beforethe addition of bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate(12 mg; 0.026 mmol; 0.047 equivalents). The solution was stirred at 25°C. for 5 minutes or until all of the bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate had dissolved. Enamide 12(100 mg, 0.55 mmol)was added via syringe. The vessel was capped and pressurized to 2.75barg (40 psig) hydrogen. After 18 hours, the mixture was diluted withhexane (4.0 mL) and filtered through silica gel to remove the catalyst.The product 13 was isolated as an oil (99% yield, 96.2% ee as determinedby chiral GC).

[0146]¹H NMR (CDCl₃) δ 4.714.65 (m, 1H); 3.71 (s, 3H); 3.55-3.47 (m,1H); 3.38-3.30 (m, 1H); 2.45-2.40 (t, 2H, J=8.4 Hz); 2.12-1.97 (m, 3H);1.74-1.64 (m, 1H); 0.94-0.89 (t, 3H, J=7.5 Hz). Chiral GC [Cyclosil-B(J&W Scientific), 40° C. for 4 min, 40° C. to 175° C. at 70° C./min,hold at 175° C. for 12 minutes]: t_(R)=23.19 (major enantiomer),t_(R)=23.24 (minor enantiomer).

Example 45 Hydrogenation of Enamide 12 to Produce Ester 13 Using Ligand(S, R)-2a

[0147] This hydrogenation was carried out as in the previous exampleexcept that ligand (S,R)-2a was used instead of (R,S)-1b. This affordedthe product 13 in 90.8% ee.

Example 46 Hydrogenation of Enamide 12 to Produce Ester 13 Using Ligand(R,S)-1b via High Pressure Hydrogenation in THF

[0148] Enamide 12 was hydrogenated according to General Procedure B inTHF as solvent using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 94.9%conversion to amino acid derivative 13 with 92.8% ee as determined bychiral GC analysis.

Example 47 Dimethyl Methylsuccinate (15a, R¹⁵=H, R¹⁶=R¹⁷=Me) usingLigand (R,S)-1a in THF at Low Pressure

[0149] Dimethyl itaconate (14a, R¹⁵=H, R¹⁶=R¹⁷=Me) was hydrogenatedaccording to General Procedure A in THF at 0.69-1.38 bars gauge (10-20psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1a (3.6 mg; 6 μmol; 0.012 equiv) for6 hours to afford 95% conversion to dimethyl methylsuccinate(15a, R¹⁵=H,R¹⁶=R¹⁷=Me) with 80.2% ee as determined by chiral GC analysis. Theanalytical properties of 15a were identical to an authentic sample.Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, film thickness0.25 μm, 90° C. isothermal, 15 psig He]: t_(R)(enantiomer 1, 15a) 17.36min, t_(R)(enantiomer 2, 15a) 17.82 min, t_(R)(14a) 23.16 min.

Example 48 Dimethyl Methylsuccinate (15a, R¹⁵=H, R¹⁶=R¹⁷=Me) usingLigand (R,S)-1a in Acetone at High Pressure

[0150] Dimethyl itaconate (14a, R¹⁵=H, R¹⁶=R⁷=Me) was hydrogenatedaccording to General Procedure B in acetone at 20.7 barg (300 psig)hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1a (3.6 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 100%conversion to dimethyl methylsuccinate(15a, R¹⁵=H, R¹⁶=R¹⁷=Me) with89.1% ee as determined by chiral GC analysis.

Example 49 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1b inTHF at Low Pressure

[0151] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure A in THF at 0.69-1.38 bars gauge (10-20psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for8 hours to afford 90.2% conversion to methyl R-lactate (R-17a, R¹⁸=H,R¹⁹=methyl) with 88.2% ee as determined by chiral GC analysis. Theanalytical properties of 17a were identical to an authentic sample.Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, film thickness0.25 μm, 75° C. isothermal, 15 psig He]: t_(R)(R-17a) 7.75 min,t_(R)(S-17a) 9.16 min, t_(R)(16a) 5.16 min.

Example 50 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1b inTHF at High Pressure

[0152] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 8 hours to afford 98.3%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 86.8% eeas determined by chiral GC analysis.

Example 51 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1b inToluene at High Pressure

[0153] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure B in toluene at 20.7 barg (300 psig)hydrogen at ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford >95%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 83.2% eeas determined by chiral GC analysis.

Example 52 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1d inTHF at Low Pressure

[0154] Methyl pyruvate (16a, R¹⁷=H, R¹⁸=methyl) was hydrogenated atambient temperature according to General Procedure A in THF at 0.69-1.38bars gauge (10-20 psig) hydrogen using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1d (3.8 mg; 6 μmol; 0.012 equiv) for 1 hour to afford 21.1%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 87.4% eeas determined by chiral GC analysis.

Example 53 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1d inTHF at High Pressure

[0155] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenated atambient temperature according to General Procedure B in THF at 20.7 barg(300 psig) hydrogen using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1d (3.8 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 98.8%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 83.8% eeas determined by chiral GC analysis.

[0156] Example 54

Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (S,R)-2e in THF at LowPressure

[0157] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenated atambient temperature according to General Procedure A in THF at 0.69-1.38bars gauge (10-20 psig) hydrogen using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for 1 hour to afford 67%conversion to methyl S-lactate (S-17a, R¹⁸=H, R¹⁹=methyl) with 91.7% eeas determined by chiral GC analysis.

Example 55 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (S,R)-2e inTHF at High Pressure

[0158] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenated atambient temperature according to General Procedure B in THF at 20.7 barg(300 psig) hydrogen using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 98.7%conversion to methyl S-lactate (S-17a, R¹⁸ =H, R¹⁹=methyl) with 88.6% eeas determined by chiral GC analysis.

Example 56 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1f inTHF at High Pressure

[0159] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1f (3.3 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.6%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 88.6% eeas determined by chiral GC analysis.

Example 57 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1g inTHF at Low Pressure

[0160] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure A in THF at 0.69-1.38 bars gauge (10-20psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for17 hours to afford 99% conversion to methyl R-lactate (R-17a, R¹⁸=H,R¹⁹=methyl) with 90.8% ee as determined by chiral GC analysis.

Example 58 Methyl Lactate (17a, R¹⁸=H, R¹⁹=Me) using Ligand (R,S)-1g inTHF at High Pressure

[0161] Methyl pyruvate (16a, R¹⁸=H, R¹⁹=methyl) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 100%conversion to methyl R-lactate (R-17a, R¹⁸=H, R¹⁹=methyl) with 88.1% eeas determined by chiral GC analysis.

Example 59 Ethyl Lactate (17b, R¹⁸=H, R¹⁹=ethyl) using Ligand (R,S)-1bin THF at High Pressure

[0162] Ethyl pyruvate (16b, R¹⁸=H, R¹⁹=ethyl) was hydrogenated accordingto General Procedure B in THF at 20.7 barg (300 psig) hydrogen atambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-lb (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 98.6%conversion to ethyl R-lactate (R-17b, R¹⁸=H, R¹⁹=ethyl) with 83.4% ee asdetermined by chiral GC analysis. The analytical properties of 17b wereidentical to an authentic sample.

[0163] Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, filmthickness 0.25 μm, 75° C. isothermal, 14 psig He]: t_(R)(R-17b) 11.40min, t_(R)(S-17b) 13.24 min, t_(R)(16b) 7.73 min.

Example 60 Ethyl Lactate (17b, R¹⁸=H, R¹⁹=ethyl) using Ligand (R,S)-1din THF at High Pressure

[0164] Ethyl pyruvate (16b, R¹⁸=H, R¹⁹=ethyl) was hydrogenated accordingto General Procedure B in THF at 20.7 barg (300 psig) hydrogen atambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1d (3.8 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.8%conversion to ethyl R-lactate (R-17b, R¹⁸=H, R¹⁹=ethyl) with 87.8% ee asdetermined by chiral GC analysis.

Example 61 Ethyl Lactate (17b, R¹⁸=H, R¹⁹=ethyl) using Ligand (S,R)-2ein THF at High Pressure

[0165] Ethyl pyruvate (16b, R¹⁸ =H, R⁹ =ethyl) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.9%conversion to ethyl S-lactate (S-17b, R¹⁸=H, R¹⁹=ethyl) with 89.8% ee asdetermined by chiral GC analysis.

Example 62 Ethyl Lactate (17b, R¹⁸=H, R¹⁹=ethyl) using Ligand (R,S)-1fin THF at High Pressure

[0166] Ethyl Pyruvate (16b, R¹⁷=H, R¹⁸=ethyl) was hydrogenated accordingto General Procedure B in THF at 20.7 barg (300 psig) hydrogen atambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1f (3.3 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.9%conversion to ethyl R-lactate (R-17b, R¹⁸=H, R¹⁹=ethyl) with 89.8% ee asdetermined by chiral GC analysis.

Example 63 Ethyl Lactate (17b, R¹⁸=H, R¹⁹=ethyl) using Ligand (R, S)-1gin THF at High Pressure

[0167] Ethyl pyruvate (16b, R¹⁸ =H, R¹⁹ =ethyl) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.9%conversion to ethyl R-lactate (R-17b, R¹⁸=H, R¹⁹=ethyl) with 90.8% ee asdetermined by chiral GC analysis.

Example 64 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (R,S)-1b in THF at High Pressure

[0168] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=Et) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1b (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 97.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate(R-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 85.2% ee as determined by chiral GCanalysis.

[0169]¹H NMR (CDCl₃) δ 7.4-7.1 (m, 5H); 4.213 (q, 1H, J=7.14 Hz); 4.15(m, 1H); 2.77 (m, 2H); 2.12 (m, 1H); 1.96 (m, 1H); 1.286 (t, 3H, J=7.14Hz). Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mm ID, filmthickness 0.25 μm, 150° C. isothermal, 18 psig He]: t_(R)(R-17c) 26.49min, t_(R)(S-17c) 27.09 min, t_(R)(¹⁶c) 23.98 min.

Example 65 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (R,S)-1c in THF at High Pressure

[0170] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=ethyl) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1c (3.8 mg; 6 μmol; 0.012 equiv) for6 hours to afford 50.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate(R-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 85.8% ee as determined by chiral GCanalysis.

Example 66 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (R,S)-1d in THF at High Pressure

[0171] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=Et) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1d (3.8 mg; 6 μmol; 0.012 equiv) for6 hours to afford 98.0% conversion to ethyl R-2-hydroxy-4-phenylbutyrate(R-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 88.6% ee as determined by chiral GCanalysis.

Example 67 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (S,R)-2e in THF at High Pressure

[0172] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=ethyl) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for6 hours to afford 97.2% conversion to ethyl S-2-hydroxy-4-phenylbutyrate(S-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 89.0% ee as determined by chiral GCanalysis.

Example 68 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (R,S)-1g in THF at Low Pressure:

[0173] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=ethyl) washydrogenated according to General Procedure A in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for24 hours to afford 65% conversion to ethyl R-2-hydroxy-4-phenylbutyrate(R-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 80.2% ee as determined by chiral GCanalysis.

Example 69 Ethyl 2-Hydroxy-4-phenylbutyrate (17c, R¹⁸=PhCH₂, R¹⁹=ethyl)using Ligand (R,S)-1g in THF at High Pressure

[0174] Ethyl 2-oxo-4-phenylbutyrate (16c, R¹⁸=PhCH₂, R¹⁹=Et) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 96.6% conversion to ethyl R-2-hydroxy-4-phenylbutyrate(R-17c, R¹⁸=PhCH₂, R¹⁹=ethyl) with 92.4% ee as determined by chiral GCanalysis.

Example 70 Methyl 2-Hydroxy-3-phenylpropionate (17d, R¹⁸=Ph, R¹⁹=methyl)using Ligand (S,R)-2e in THF at High Pressure

[0175] Methyl 2-oxo-3-phenylpropionate (16d, R¹⁸=Ph, R¹⁹=methyl) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R¹⁸=Ph,R¹⁹=methyl) with 83.2% ee as determined by chiral GC analysis.

[0176]¹H NMR (DMSO-d₆) δ 7.3-7.1 (m, 5H); 5.547 (d, 1H, J=6.04 Hz); 4.22(m, 1H); 3.584 (s, 3H); 2.923 (dd, 1H, J=5.22, 13.74 Hz); 2.289 (dd, 1H,J=8.24,13.74 Hz). Chiral GC [Cyclosil-B (J&W Scientific) 30 m×0.25 mmID, film thickness 0.25 μm, 140° C. isothermal, 18 psig He]:t_(R)(enantiomer 1, 17d) 19.62 min, t_(R)(enantiomer 2, 17d) 21.54 min,t_(R)(16d) 18.54 min.

Example 71 Methyl 2-Hydroxy-3-phenylpropionate (17d, R¹⁸=Ph, R¹⁹=methyl)using Ligand (R,S)-1f in THF at High Pressure

[0177] Methyl 2-oxo-3-phenylpropionate (16d, R¹⁸=Ph, R¹⁹=methyl) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1f (3.3 mg; 6 μmol; 0.012 equiv) for6 hours to afford methyl 2-hydroxy-3-phenylpropionate (17d, R¹⁸=Ph,R¹⁹=methyl) with 86.0% ee as determined by chiral GC analysis.

Example 72 Methyl 2-Hydroxy-3-phenylpropionate (17d, R¹⁸=Ph, R¹⁹=methyl)using Ligand (R,S)-1g in THF at High Pressure

[0178] Methyl 2-oxo-3-phenylpropionate (16d, R¹⁸=Ph, R¹⁹=methyl) washydrogenated according to General Procedure B in THF at 20.7 barg (300psig) hydrogen at ambient temperature usingbis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5μmol; 0.01 equiv) and ligand (R,S)-1g (3.7 mg; 6 μmol; 0.012 equiv) for6 hours to afford 30% conversion to methyl 2-hydroxy-3-phenylpropionate(17d, R¹⁸=Ph, R¹⁹methyl) with 85.4% ee as determined by chiral GCanalysis.

Example 73 2-Hydroxy-3,3-dimethyl-γ-butyrolactone (19) using Ligand(S,R)-2e in THF at High Pressure

[0179] 2-Oxo-3,3-dimethyl-γ-butyrolactone (18) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2e (3.1 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.0%conversion to 2-hydroxy-3,3-dimethyl-y-butyrolactone (19) with 95.0% eeas determined by chiral GC analysis.

[0180]¹H NMR (CDCl₃) δ 4.114 (s, 1H); 4.023 (d, 1H, J=8.52 Hz); 3.936(d, 1H, J=8.52 Hz); 1.223 (s, 3H); 1.071 (s, 3H). Chiral GC [Cyclosil-B(J&W Scientific) 30 m×0.25 mm ID, film thickness 0.25 μm, 140° C.isothermal, 14 psig He]: t_(R)(enantiomer 1, 19) 11.18 min,t_(R)(enantiomer 2, 19) 11.66 min, t_(R)(18) 7.99 min.

Example 74 2-Hydroxy-3,3-dimethyl-γ-butyrolactone (19) using Ligand(S,R)-2f in THF at High Pressure

[0181] 2-Oxo-3,3-dimethyl-y-butyrolactone (18) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2f (3.3 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.6%conversion to 2-hydroxy-3,3-dimethyl-γ-butyrolactone (19) with 96.6% eeas determined by chiral GC analysis.

Example 75 2-Hydroxy-3, 3-dimethyl-γ-butyrolactone (19) using Ligand (S,R)-2g in THF

[0182] 2-Oxo-3,3-dimethyl-γ-butyrolactone (18) was hydrogenatedaccording to General Procedure B in THF at 20.7 barg (300 psig) hydrogenat ambient temperature using bis(1,5-cyclooctadiene)rhodiumtrifluoromethanesulfonate (2.3 mg; 5 μmol; 0.01 equiv) and ligand(S,R)-2g (3.7 mg; 6 μmol; 0.012 equiv) for 6 hours to afford 99.6%conversion to 2-hydroxy-3,3-dimethyl-γ-butyrolactone (19) with 97.2% eeas determined by chiral GC analysis.

[0183] The invention has been described in detail with particularreference to preferred embodiments thereof, but it will be understoodthat variations and modifications can be effected within the spirit andscope of the invention.

We claim:
 1. A substantially enantiomerically pure bis-phosphinecompound comprising a substantially enantiomerically pure chiralbackbone linking two phosphines residues wherein one of the phosphineresidues has three phosphorus-carbon bonds and the other phosphineresidue has two phosphorus-carbon bonds and one phosphorus-nitrogen bondwherein the nitrogen is part of the chiral backbone.
 2. A substantiallyenantiomerically pure compound according to claim 1 having formula 1:

wherein R is selected from substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen; R¹, R², R³, R⁴, and R⁵are independently selected from hydrogen, substituted and unsubstituted,branched- and straight-chain C₁-C₂₀ alkyl, substituted and unsubstitutedC₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl,and substituted and unsubstituted C₄-C₂₀ heteroaryl wherein theheteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3;m is 0 to 5; and M is selected from the metals of Groups IVB, VB, VIB,VIIB and VIII.
 3. A compound according to claim 2 wherein R is methyl,R² is phenyl, ethyl, isopropyl, or cyclohexyl, R³ is phenyl, n and m are0, and M is iron, ruthenium, or osmium.
 4. A compound according to claim3 where R¹ is hydrogen, methyl, ethyl, or n-propyl and M is iron.
 5. Asubstantially enantiomerically pure compound according to claim 1 havingformula 2:

wherein R is selected from substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen; R¹, R², R³, R⁴, and R⁵are independently selected from hydrogen, substituted and unsubstituted,branched- and straight-chain C₁-C₂₀ alkyl, substituted and unsubstitutedC₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl,and substituted and unsubstituted C₄-C₂₀ heteroaryl wherein theheteroatoms are selected from sulfur, nitrogen, and oxygen; n is 0 to 3;m is 0 to 5; and M is selected from the metals of Groups IVB, VB, VIB,VIIB and VIII.
 6. A compound according to claim 5 where R is methyl, R²is phenyl, ethyl, isopropyl, or cyclohexyl, R³ is phenyl, n and m are 0,and M is iron, ruthenium, or osmium.
 7. A compound according to claim 6where R¹ is hydrogen, methyl, ethyl, or n-propyl and M is iron.
 8. Acompound comprising a substantially enantiomerically pure bis-phosphinecompound defined in claim 1 in complex association with a Group VIIImetal.
 9. A compound comprising a substantially enantiomerically purecompound defined in claim 2 in complex association with a Group VIIImetal.
 10. A compound according to claim 9 wherein (i) in thesubstantially enantiomerically pure compound defined in claim 2 R ismethyl, R¹ is hydrogen, methyl, ethyl, or n-propyl, R² is phenyl, ethyl,isopropyl, or cyclohexyl, R³ is phenyl, n and m are 0, and M is iron,ruthenium, or osmium and (ii) the Group VIII metal is rhodium, iridiumor ruthenium.
 11. A compound comprising a substantially enantiomericallypure compound defined in claim 5 in complex association with a GroupVIII metal.
 12. A compound according to claim 11 wherein (i) in thesubstantially enantiomerically pure compound defined in claim 5 R ismethyl, R¹ is hydrogen, methyl, ethyl, or n-propyl, R² is phenyl, ethyl,isopropyl, or cyclohexyl, R³ is phenyl, n and m are 0, and M is iron,ruthenium, or osmium and (ii) the Group VIII metal is rhodium, iridiumor ruthenium.
 13. A process for the preparation of a substantiallyenantiomerically pure compound having formula 1:

which comprises the steps of: (1) contacting a dialkylamine havingformula 3:

 with a carboxylic anhydride having the formula (R¹⁰CO)₂O to obtain anester compound having formula 4:

(2) contacting the ester produced in step (1) with an amine having theformula H₂N—R¹ to obtain an intermediate compound having formula 5:

(3) contacting intermediate compound 5 with a halophosphine having theformula X—P(R²)₂; wherein R, R⁸, and R⁹ are independently selected fromsubstituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, substituted and unsubstituted C₃-C₈ cycloalkyl, substituted andunsubstituted C₆-C₂₀ carbocyclic aryl, and substituted or unsubstitutedC₄-C₂₀ heteroaryl wherein the heteroatoms are selected from sulfur,nitrogen, and oxygen; R¹, R², R³, R⁴, and R⁵ are independently selectedfrom hydrogen, substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen; n is 0 to 3; m is 0 to5; M is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII;R¹⁰ is a C₁ to C₄ alkyl radical; and X is chlorine, bromine, or iodine.14. A process according to claim 13 wherein R, R⁸, and R⁹ are methyl, R²is phenyl, ethyl, isopropyl, or cyclohexyl, R³ is phenyl, X is chlorineor bromine, n and m are 0, and M is iron, ruthenium, or osmium.
 15. Aprocess according to claim 14 where R¹ is hydrogen, methyl, ethyl, orn-propyl, X is chlorine, and M is iron.
 16. A process according to claim13 wherein the carboxylic anhydride is selected from acetic, propionic,or butyric anhydride and the lower alcohol solvent is selected frommethanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, ortert-butanol.
 17. A process according to claim 16 wherein step (3) iscarried out in the presence of a C₃-C₁₅ trialkylamine and a non-polar,aprotic solvent selected from aliphatic and aromatic hydrocarbonscontaining 6 to 10 carbon atoms, halogenated hydrocarbons containing upto about 6 carbon atoms, and cyclic and acyclic ethers containing fromabout 4 to 8 carbon atoms.
 18. A process according to claim 17 whereinstep (3) is carried out in the presence of triethylamine and toluene.19. A process for the preparation of a substantially enantiomericallypure compound having formula 2:

which comprises the steps of: (1) contacting a dialkylamine havingformula 6:

 with a carboxylic anhydride having the formula (R¹⁰CO)₂O to obtain anester compound having formula 7:

(2) contacting the ester produced in step (1) with an amine having theformula H₂N—R¹ to obtain an intermediate compound having formula 8:

(3) contacting intermediate compound 8 with a halophosphine having theformula X—P(R²)₂; wherein R, R⁸, and R⁹ are independently selected fromsubstituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, substituted and unsubstituted C₃-C₈ cycloalkyl, substituted andunsubstituted C₆-C₂₀ carbocyclic aryl, and substituted and unsubstitutedC₄-C₂₀ heteroaryl wherein the heteroatoms are selected from sulfur,nitrogen, and oxygen; R¹, R², R³, R⁴, and R⁵ are independently selectedfrom hydrogen, substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen; n is 0 to 3; m is 0 to5; M is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII;R¹⁰ is a C₁ to C₄ alkyl radical; and X is chlorine, bromine, or iodine.20. A process according to claim 19 wherein R, R⁸, and R⁹ are methyl, R²is phenyl, ethyl, isopropyl, or cyclohexyl, R³ is phenyl, X is chlorineor bromine, n and m are 0, and M is iron, ruthenium, or osmium.
 21. Aprocess according to claim 20 wherein R¹ is hydrogen, methyl, ethyl, orn-propyl, X is chlorine, and M is iron.
 22. A process according to claim19 wherein the carboxylic anhydride is selected from acetic, propionic,or butyric anhydride and the lower alcohol solvent is selected frommethanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, ortert-butanol.
 23. A process according to claim 22 wherein step (3) iscarried out in the presence of a C₃-C₁₅ trialkylamine and a non-polar,aprotic solvent selected from aliphatic and aromatic hydrocarbonscontaining 6 to 10 carbon atoms, halogenated hydrocarbons containing upto about 6 carbon atoms, and cyclic and acyclic ethers containing fromabout 4 to 8 carbon atoms.
 24. A process according to claim 22 whereinstep (3) is carried out in the presence of triethylamine and toluene.25. An amino-phosphine compound having the formula

wherein R and R¹ are independently selected from substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀carbocyclic aryl, and substituted and unsubstituted C₄-C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;R³, R⁴, and R⁵ are independently selected from hydrogen, substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, substitutedand unsubstituted C₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀carbocyclic aryl, and substituted and unsubstituted C₄-C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;n is 0 to 3; m is 0 to 5; and M is selected from the metals of GroupsIVB, VB, VIB, VIIB and VIII.
 26. A compound according to claim 25wherein R is methyl, R¹ is methyl, ethyl, or n-propyl, R³ is phenyl, nand m are 0, and M is iron, ruthenium, or osmium.
 27. An amino-phosphinecompound having the formula

wherein R and R¹ are independently selected from substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, substitutedand unsubstituted C₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀carbocyclic aryl, and substituted and unsubstituted C₄-C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;R³, R⁴, and R⁵ are independently selected from hydrogen, substituted andunsubstituted, branched- and straight-chain C₁-C₂₀ alkyl, substitutedand unsubstituted C₃-C₈ cycloalkyl, substituted and unsubstituted C₆-C₂₀carbocyclic aryl, and substituted and unsubstituted C₄-C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;n is 0 to 3; m is 0 to 5; and M is selected from the metals of GroupsIVB, VB, VIB, VIIB and VIII.
 28. A compound according to claim 27wherein R is methyl, R¹ is methyl, ethyl, or n-propyl, R³ is phenyl, nand m are 0, and M is iron, ruthenium, or osmium.
 29. A method for theenantioselective hydrogenation of a hydrogenatable compound whichcomprises contacting the hydrogenatable compound with hydrogen in thepresence of a catalyst complex defined in any of claims 8 through 12.30. A method according to claim 29 wherein the hydrogenatable compoundcontains the residue C═C(N—C═O)—C═O.
 31. A method according to claim 30wherein the hydrogenatable compound has formula 10:

wherein: R¹¹, R¹², and R¹⁴ are independently selected from hydrogen,substituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, substituted and unsubstituted C₃-C₈ cycloalkyl, substituted andunsubstituted C₆-C₂₀ carbocyclic aryl, and substituted and unsubstitutedC₄-C₂₀ heteroaryl wherein the heteroatoms are selected from sulfur,nitrogen, and oxygen; and R¹³ is selected from hydrogen, substituted andunsubstituted C₁ to C₂₀ alkyl, substituted and unsubstituted C₁ to C₂₀alkoxy, substituted and unsubstituted C₃ to C₈ cycloalkyl, substitutedand unsubstituted C₃ to C₈ cycloalkoxy, substituted and unsubstitutedcarbocyclic C₆ to C₂₀ aryl, substituted and unsubstituted carbocyclic C₆to C₂₀ aryloxy, substituted and unsubstituted C₄ to C₂₀ heteroarylwherein the heteroatoms are selected from sulfur, nitrogen, and oxygenand substituted and unsubstituted C₄ to C₂₀ heteroaryloxy wherein theheteroatoms are selected from sulfur, nitrogen, and oxygen; or R¹³ andsR¹⁴ collectively represent a substituted or unsubstituted alkylene groupof 1-4 chain carbon atoms forming a lactam.
 32. A method according toclaim 29 wherein the hydrogenatable compound has formula 14:

wherein: R¹⁵ is selected from hydrogen, substituted and unsubstituted,branched- and straight-chain C₁-C₂₀ alkyl, and substituted andunsubstituted C₃-C₈ cycloalkyl, and R¹⁶ and R¹⁷ are independentlyselected from hydrogen, substituted and unsubstituted, branched- andstraight-chain C₁-C₂₀ alkyl, substituted and unsubstituted C₃-C₈cycloalkyl, substituted and unsubstituted C₆-C₂₀ carbocyclic aryl, andsubstituted and unsubstituted C₄-C₂₀ heteroaryl wherein the heteroatomsare selected from sulfur, nitrogen, and oxygen.
 33. A method accordingto claim 29 wherein the hydrogenatable compound has formula 16:

wherein: R¹⁸ and R¹⁹ are independently selected from hydrogen,substituted and unsubstituted, branched- and straight-chain C₁-C₂₀alkyl, and substituted and unsubstituted C₃-C₈ cycloalkyl, substitutedand unsubstituted C₆-C₂₀ carbocyclic aryl, and substituted andunsubstituted C₄-C₂₀ heteroaryl wherein the heteroatoms are selectedfrom sulfur, nitrogen, or oxygen; or R¹⁸ and R¹⁹ collectively representa substituted or unsubstituted alkylene group of 1-4 chain carbon atomsforming an α-ketolactone.